HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes

Abstract

Cytotoxic T lymphocytes (CTLs) lyse virally infected cells that display viral peptide epitopes in association with major histocompatibility complex (MHC) class I molecules on the cell surface. However, despite a strong CTL response directed against viral epitopes, untreated people infected with the human immunodeficiency virus (HIV-1) develop AIDS. To resolve this enigma, we have examined the ability of CTLs to recognize and kill infected primary T lymphocytes. We found that CTLs inefficiently lysed primary cells infected with HIV-1 if the viral nef gene product was expressed. Resistance of infected cells to CTL killing correlated with nef-mediated downregulation of MHC class I and could be overcome by adding an excess of the relevant HIV-1 epitope as soluble peptide. Thus, Nef protected infected cells by reducing the epitope density on their surface. This effect of nef may allow evasion of CTL lysis by HIV-1-infected cells.

To kill or be killed: how HIV exhausts the immune system

“…72 HIV strategies to protect lymphocytes from apoptosis include: (1) the upregulation of Bcl-2 and downmodulation of Bax by Vpr; 81 (2) the promotion of cell cycle progression, and subsequent increased virus production, by Tat-dependent inhibition of p53 transcription; 82 (3) the downregulation by Nef and gp120 of expression of the CD4 receptor by infected cells, thereby preventing subsequent gp120-CD4-mediated apoptosis; [83][84][85] and (4) the downmodulation by Vpu and Nef of the expression of MHC class I molecules and the upregulation of CD95L expression on infected cells, a strategy that might function to protect infected cells from cytolysis by CTL or NK cells. 86,87 These in vitro data are in line with in vivo observations showing that, in lymph-node biopsies from HIV-infected humans and SIV-infected monkeys, productively infected cells are not apoptotic, indicating that they are relatively resistant to direct HIV-induced killing in vivo. 31 Collectively, these data indicate that HIV can manipulate cellular apoptotic machinery, destroying the immune system through the activation of apoptotic programs in lymphocytes, but ensuring viral survival by manipulating the apoptotic machinery to its advantage in infected cells.…”

“…Nef downmodulates the expression of MHC class I molecules and upregulates CD95L expression on infected cells, a strategy that may function to protect infected cells from cytolysis by CTL or NK cells. 115,116 Nef, gp120 and Vpu contribute to the downregulation of CD4 receptor on infected cells, preventing subsequent gp120-CD4-mediated apoptosis. [117][118][119] The relative resistance to direct HIV-induced killing of infected cells is confirmed by in vivo studies on lymph node biopsies from HIV þ individuals, showing that productively infected cells are not apoptotic, in contrast to uninfected cells.…”

Direct Priming and Cross-Priming Contribute Differentially to the Induction of CD8+ CTL Following Exposure to Vaccinia Virus Via Different Routes

“…Recently, it has been proposed that another HCMV product, UL16, serves to mask NK recognition of UL16-binding proteins or MHC class I chain-related protein B, which are ligands for the activating receptor, NKG2D/DAP10 (50). In the case of HIV-1, the Nef protein down-regulates cell surface MHC class I by accelerating the endocytosis of class I complexes (51)(52)(53)(54). The specific targeting of HLA-A and -B locus products, but not HLA-C or -E locus products, may be relevant for NK cell evasion (55).…”

Engineering HIV-Resistant, Anti-HIV Chimeric Antigen Receptor T Cells

“…[7][8][9][10][11] Because residual HIV expression continues despite effective ART [12][13][14][15][16] and is required for viral rebound, HIV-infected cells should theoretically be targetable by a T cell therapeutic agent. Several mechanisms are thought to be responsible for the apparent failure of autologous cytotoxic T lymphocytes (CTLs) to clear reactivated cells in HIV-infected individuals: HIV evolution prior to ART quickly selects for CTL escape mutations; [17][18][19] HIV Nef mediates downregulation of major histocompatibility complex class I (MHC-I), 20,21 protecting HIV-infected cells from T cell receptor (TCR)-dependent CTL killing; and HIV-specific CTL responses may be limited by exhaustion 22,23 or peripheral immune tolerance. 24,25 Over the last decade, major advances have been made in engineering human T cells via introduction of chimeric antigen receptors (CARs) to enable specific lysis of pathogenic targets.…”